Homozygous deletion of chromodomain helicase DNA binding protein 1 (CHD1) is among the most frequent genetic alterations in prostate cancer. CHD1 is converted from a non-essential to an essential gene for prostate cancer cell survival when phosphatase and tensin homolog (PTEN), another frequently deleted gene in prostate cancer, is disrupted. It remains unknown whether this PTEN-CHD1 genetic and functional relationship also operates in other solid tumors. Here, we address this question by using genetically engineered mouse models. Inducible deletion of Pten and p53 in all somatic cells of adult mice led to widespread PI3K/Akt pathway activation and hyperplastic phenotypes, causing multi-organ failure and lethality. Remarkably, when Chd1 was co-deleted in the Pten/p53 model, the lethality remained unperturbed. At the protein level, Chd1 was stabilized upon Pten deletion in prostate, but not in other organs examined (lung, liver, kidney, colon, mammary). These results shed mechanistic insight on the cancer type-specific copy number alteration pattern of PTEN and CHD1.